Lexxel

WARNINGS

Anaphylactoid and Possibly Related Reactions - Presumably because angiotensin-converting
enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including
endogenous bradykinin, patients receiving ACE inhibitors (including LEXXEL (enalapril maleate-felodipine) )
may be subject to a variety of adverse reactions, some of them serious.

Angioedema: Angioedema of the face, extremities, lips, tongue, glottis,
and/or larynx has been reported in patients treated with angiotensin converting
enzyme inhibitors, including enalapril. This may occur at any time during treatment.
In such cases LEXXEL (enalapril maleate-felodipine) should be promptly discontinued, and appropriate therapy
and monitoring should be provided until complete and sustained resolution of
signs and symptoms has occurred. In instances where swelling has been confined
to the face and lips the condition has generally resolved without treatment,
although antihistamines have been useful in relieving symptoms. Angioedema associated
with laryngealedema may be fatal. Where there is involvement of the tongue,
glottis or larynx, likely to cause airway obstruction, appropriate therapy,
e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures
necessary to ensure a patent airway, should be promptly provided. (See ADVERSE
REACTIONS.)

Patients with a history of angioedema unrelated to ACE inhibitor therapy may
be at increased risk of angioedema while receiving an ACE inhibitor (see also
INDICATIONS AND USAGE and CONTRAINDICATIONS).

Anaphylactoid Reactions During Desensitization: Two patients undergoing
desensitizing treatment with hymenoptera venom while receiving ACE inhibitors
sustained life- threatening anaphylactoid reactions. In the same patients, these
reactions were avoided when ACE inhibitors were temporarily withheld, but they
reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions
have been reported in patients dialyzed with high-flux membranes and treated
concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been
reported in patients undergoing low-density lipoproteinapheresis with dextran
sulfate absorption.

Excessive hypotension is rare in uncomplicated hypertensive patients treated
with enalapril alone. Patients at risk for excessive hypotension, sometimes
associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics:
heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis
or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion
of any etiology. It may be advisable to eliminate the diuretic (except in patients
with heart failure), reduce the diuretic dose or increase salt intake cautiously
before initiating therapy with enalapril maleate in patients at risk for excessive
hypotension who are able to tolerate such adjustments. (See PRECAUTIONS:DRUG INTERACTIONS and ADVERSE
REACTIONS.) In patients at risk for excessive hypotension, therapy should
be started under very close medical supervision and such patients should be
followed closely for the first 2 weeks of treatment and whenever the dose of
enalapril and/or diuretic is increased. Similar considerations may apply to
patients with ischemic heart or cerebrovascular disease, in whom an excessive
fall in blood pressure could result in a myocardial infarction or cerebrovascular
accident.

If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of enalapril maleate, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of enalapril or diuretic may be necessary.

Felodipine, like other calcium channel blockers, may occasionally precipitate significant hypotension and rarely syncope. It may lead to reflex tachycardia which in susceptible individuals may precipitate angina pectoris. (See ADVERSE REACTIONS.)

Neutropenia/Agranulocytosis - Another angiotensin converting enzyme
inhibitor, captopril, has been shown to cause agranulocytosis and bone marrowdepression, rarely in uncomplicated patients but more frequently in patients
with renal impairment, especially if they also have a collagenvascular disease.
Available data from clinical trials of enalapril are insufficient to show that
enalapril does not cause agranulocytosis at similar rates. Marketing experience
has revealed cases of neutropenia or agranulocytosis in which a causal relationship
to enalapril cannot be excluded. Periodic monitoring of white blood cell counts
in patients with collagen vascular disease and renal disease should be considered.

Hepatic Failure - Rarely, ACE inhibitors have been associated with a
syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic
necrosis and (sometimes) death. The mechanism of this syndrome is not understood.
Patients receiving ACE inhibitors who develop jaundice or marked elevations
of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate
medical follow-up.

Fetal/Neonatal Morbidity and Mortality - ACE inhibitors can cause fetal
and neonatal morbidity and death when administered to pregnant women. Several
dozen cases have been reported in the world literature. When pregnancy is detected,
LEXXEL (enalapril maleate-felodipine) should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.

These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of LEXXEL (enalapril maleate-felodipine) as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, LEXXEL (enalapril maleate-felodipine) should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.

No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD).

In rats administered the combination of enalapril and felodipine (enalapril [E]=1.9-felodipine [F]=2.5 mg/kg/day), an increased incidence of fetuses with dilated renal pelvis/ureter was observed. However, there was no evidence of this effect in the offspring postweaning. In mice, with doses of E=23, F=30 mg/kg/day or greater, there was an increased incidence of both early and late in utero deaths. Other than a transient and slight decrease in body weight gain in the first generation offspring, there were no adverse effects in offspring with regard to sexual maturation, behavioral development, fertility or fecundity.

Enalapril-felodipine given to pregnant mice (enalapril 20.8, felodipine 27 mg/kg/day) and rats (enalapril =17.3, felodipine =22.5 mg/kg/day) produced plasma levels (Cmax and AUC values) of enalapril/enalaprilat that were 76 to 418-fold greater and plasma levels of felodipine that were 151 to 433-fold greater than those expected in humans (non- pregnant) at the dose to be used in humans.

PRECAUTIONS

General:

Aortic Stenosis/Hypertrophic Cardiomyopathy - As with all vasodilators,
enalapril should be given with caution to patients with obstruction in the outflow
tract of the left ventricle.

Impaired Renal Function - As a consequence of inhibiting the
renin-angiotensin-aldosterone system, changes in renal function may be anticipated
in susceptible individuals treated with enalapril. In patients with severe heart
failure whose renal function may depend on the activity of the renin- angiotensin-aldosterone
system, treatment with angiotensin converting enzyme inhibitors, including enalapril,
may be associated with oliguria and/or progressive azotemia and rarely with
acute renal failure and/or death.

In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20% of patients treated with enalapril. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some enalapril-treated patients with hypertension or heart failure, with no apparent pre-existing renal vascular disease, have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of enalapril or discontinuation of the diuretic may be required.

Evaluation of the hypertensive patient should always include assessment
of renal function.

Hyperkalemia - Elevated serum potassium (greater than 5.7 mEq/L)
was observed in approximately 1% of hypertensive patients in clinical trials
treated with enalapril alone. In most cases these were isolated values which
resolved despite continued therapy. Hyperkalemia was a cause of discontinuation
of therapy in 0.28% of hypertensive patients. In clinical trials in heart failure,
hyperkalemia was observed in 3.8% of patients but was not a cause for discontinuation.

Risk factors for the development of hyperkalemia include renal insufficiency,
diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium
supplements and/or potassium-containing salt substitutes, which should be used
cautiously, if at all, with enalapril. (See :DRUG
INTERACTIONS.)

Elderly Patients or Patients with Impaired Liver Function - Patients
over 65 years of age or patients with impaired liver function may have elevated
plasma concentrations of felodipine. (See DOSAGE
AND ADMINISTRATION.)

Cough - Presumably due to the inhibition of the degradation of
endogenous bradykinin, persistent nonproductive cough has been reported with
all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced
cough should be considered in the diagnosis of cough.

Surgery/Anesthesia - In patients undergoing major surgery or
during anesthesia with agents that produce hypotension, enalapril may block
angiotensin II formation secondary to compensatory renin release. If hypotension
occurs and is considered to be due to this mechanism, it can be corrected by
volume expansion.

Peripheral Edema- Peripheral edema, generally mild and not associated
with generalized fluid retention, was the most common adverse event in the felodipine
clinical trials. The incidence of peripheral edema was both dose and age dependent.
This adverse event generally occurs within 2-3 weeks of the initiation of treatment.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term carcinogenicity tests have been performed with the combination. Enalapril-felodipine was not mutagenic with or without metabolic activation in vitro in the Ames microbial mutation assay, the V-79 mammalian cell forward mutation assay, the alkaline elution assay with rat hepatocytes or the CHO mammalian cell cytogenetics assay. An in vivo mouse bone marrow cytogenetics assay was also negative.

In rats given enalapril-felodipine, there was no effect on fertility in males at doses up to 6.9/9 mg/kg/day, and in females at doses up to 17.3/22.5 mg/kg/day.

There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis.

Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.

There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis).

In a 2-year carcinogenicity study in rats fed felodipine at doses of 7.7, 23.1 or 69.3 mg/kg/day (up to 61 times† the maximum recommended human dose on a mg/m2 basis), a dose-related increase in the incidence of benign interstitial cell tumors of the testes (Leydig cell tumors) was observed in treated male rats. These tumors were not observed in a similar study in mice at doses up to 138.6 mg/kg/day (61 times† the maximum recommended human dose on a mg/m2 basis). Felodipine, at the doses employed in the 2-year rat study, has been shown to lower testicular testosterone and to produce a corresponding increase in serum luteinizing hormone in rats. The Leydig cell tumor development is possibly secondary to these hormonal effects which have not been observed in man.

In this same rat study, a dose-related increase in the incidence of focal squamous cell hyperplasia, compared to control, was observed in the esophageal groove of male and female rats in all dose groups. No other drug-related esophageal or gastricpathology was observed in the rats or with chronic administration in mice and dogs. The latter species, like man, has no anatomical structure comparable to the esophageal groove.

Felodipine was not carcinogenic when fed to mice at doses of up to 138.6 mg/kg/day (61 times† the maximum recommended human dose on a mg/m2 basis) for periods of up to 80 weeks in males and 99 weeks in females.

Felodipine did not display any mutagenic activity in vitro in the Ames microbial mutagenicity test or in the mouse lymphoma forward mutation assay. No clastogenic potential was seen in vivo in the mouse micronucleus test at oral doses up to 2500 mg/kg (1100 times† the maximum recommended human dose on a mg/m2 basis) or in vitro in a human lymphocytechromosomeaberration assay.

A fertility study in which male and female rats were administered doses of 3.8, 9.6, or 26.9 mg/kg/day (up to 24 times† the maximum recommended human dose on a mg/m2 basis) showed no significant effect of felodipine on reproductive performance.

Pregnancy

Teratogenic Effects- Studies in pregnant rabbits administered
doses of felodipine 0.46, 1.2, 2.3, and 4.6 mg/kg/day (from 0.8 to 8 times†
the maximum recommended human dose on a mg/m2 basis) showed digital
anomalies consisting of reduction in size and degree of ossification of the
terminal phalanges in the fetuses. The frequency and severity of the changes
appeared dose-related and were noted even at the lowest dose. These changes
have been shown to occur with other members of the dihydropyridine class and
are possibly a result of compromised uterine blood flow. Similar fetal anomalies
were not observed in rats given felodipine.

In a teratology study in cynomolgus monkeys, no reduction in the size of the terminal phalanges was observed, but an abnormal position of the distal phalanges was noted in about 40% of the fetuses.

Nonteratogenic Effects- A prolongation of parturition with difficult
labor and an increased frequency of fetal and early postnatal deaths were observed
in rats administered felodipine doses of 9.6 mg/kg/day (8 times† the maximum
human dose on a mg/m2 basis) and above.

Significant enlargement of the mammary glands, in excess of the normal enlargement for pregnant rabbits, was found with doses greater than or equal to 1.2 mg/kg/day (2.1 times the maximum human dose on a mg/m2 basis). This effect occurred only in pregnant rabbits and regressed during lactation. Similar changes in the mammary glands were not observed in rats or monkeys.

There are no adequate and well-controlled studies with felodipine in pregnant women. If felodipine is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus, possible digital anomalies of the infant, and the potential effects of felodipine on labor and delivery, and on the mammary glands of pregnant females.

Nursing Mothers:

Enalapril and enalaprilat are detected in human breast milk. It is not known whether felodipine administered as monotherapy is secreted in human milk; studies of the combination of enalapril and felodipine in rats indicate that felodipine concentrates in milk to a level almost ten-fold that found in plasma.

Because of the potential for serious adverse reactions from enalapril and felodipine in the infant, a decision should be made either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Therefore, caution should be exercised when LEXXEL (enalapril maleate-felodipine) is given to a nursing mother.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use:

Clinical studies of LEXXEL (enalapril maleate-felodipine) did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. Elderly patients may have elevated
plasma concentrations of felodipine and may respond to lower doses of felodipine.
In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease
or other drug therapy (see CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION for information
on the individual components of LEXXEL (enalapril maleate-felodipine) ).

This drug is known to be substantially excreted by the kidney, and the risk
of toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal function,
care should be taken in dose selection. Evaluation of the hypertensive patient
should always include assessment of renal function (see CLINICAL
PHARMACOLOGY).

† Based on patient weight of 50 kg

Last reviewed on RxList: 10/25/2007
This monograph has been modified to include the generic and brand name in many instances.